Epigenetics is the study of information within the cell that is heritable during cell division, but does not lie within the DNA sequence itself. Epigenetics has been largely ignored in human genomic science, although there is reason to believe that common human diseases may be related to epigenetic modifiers. Except for cancer genetics, where one can compare the disease to normal tissue from the same individual, there have been no systematic approaches toward identifying the epigenetic basis of common human disease, and indeed the human genome project is essentially devoid of any epigenetic information to date. Our goal is to develop the tools and paradigms for the nascent area of medical epigenetics, including epigenome discovery, its quantitative analysis, and its application to medicine. The first aim is to develop high throughput tools for epigenome analysis, high throughput approaches to allele-specific gene expression and methylation analysis, and computational approaches to identifying epigenetic marks through comparative sequencing. The second aim is to develop a novel field of quantitative epigenetics, including a novel epigenetic transmission test, an innovative approach to quantitative epigenotype-quantitative phenotype association, and a new approach to genetic linkage in which the epigenotype is treated mathematically as a quantitative phenotype to identify conventional genetic variants that influence epigenetic phenomena. The third aim is to apply these tools to the epigenetics of common human disease, using epidemiological approaches that interface between these quantitative epigenetic tools and defined populations: a large Icelandic population that will allow assessment of stability of epigenetic marks over time; a large number of bipolar disorder families to test evidence of epigenetic effects on chromosomes 18 and 22; and autism families to test evidence of epigenetic effects on chromosomes 7 and 15. The investigators all have a strong record of past and recent accomplishments in genetics and genomics, including technical novelty, and we have already united in significant ways in preparing this proposal. The Center also has a strong focus on training interdisciplinary investigators in this new area, who will often work in more than one cooperating laboratory. Finally, we have taken a highly innovative approach to the Minority Action Plan, developed for recruiting gifted minority children through the Center for Talented Youth at Johns Hopkins, and providing longitudinal training opportunities in genomic science through college. We believe our Center will have a major impact in genomic science in providing a foundation for this novel, important, and exciting field.